The present invention concerns an agent for treating ischemic disease. A typical ischemic disease, obstructive arteriosclerosis, will be described first.
Obstructive arteriosclerosis is a disease in which an arteriosclerotic lesion results in occlusion or stenosis of a major truncal artery in the extremity, especially in the lower limb, causing an ischemic disorder to its periphery. Clinical symptoms of this disease are classified as coldness or numbness, intermittent claudication, rest pain, and ulcer/necrosis. In Japan, patients with obstructive arteriosclerosis are estimated to number about 100,000 (Yusuke Tada: Biomedicine & Therapeutics, Vol. 31, 289-292; 1997). The number of patients with this disease is expected to increase because of the increase in the elderly population and the westernization of diets. Therapies of obstructive arteriosclerosis include kinesitherapy or exercise therapy, pharmacotherapy, and revascularization, which are selected depending on symptoms or the patient's condition. Recently, gene therapy and intramuscular transplantation of bone marrow cells have also been attempted.
The above-described therapies are currently achieving some success in the treatment of obstructive arteriosclerosis, but the respective therapies involve the following problems. While exercise therapy has increased the distance (a patient can walk) of walking in some mild cases, the effect of this therapy is difficult to predict. Moreover, patients are not satisfied with the increase in the walking distance, if any, and 30% of them are reported to have requested revascularization (Takashi Ohta: Japan Medical Journal, Vol. 3935, 25-29, 1999). At present, exercise therapy is not a very effective form of treatment.
In pharmacotherapy, antiplatelet agents are mainly prescribed, but they merely prevent an aggravation of symptoms. Microcirculation improving agents and oxygen transport improving agents, which have recently been developed aggressively, are only expected to be indicated for mild cases. At present, there are no radical therapeutic agents available for obstructive arteriosclerosis.
Revascularization, on the other hand, is currently the most effective therapy, which involves percutaneous angioplasty or a bypass operation depending on the condition of the patient or the location or severity of the lesion. These surgical operations are so extensive as to pose problems, such as surgery-associated complications or deaths, and a poor prognosis for a long life.
With gene therapy, treatment is provided using genes of angiogenic factors, such as vascular endothelial cell growth factor and epidermal cell growth factor. However, this therapy is still at the experimental stage, and evaluations of its safety and efficacy have not been established. Thus, gene therapy has not spread generally.
Intramuscular transplantation of bone marrow cells, whose therapeutic effects have recently been reported, is a therapy in which bone marrow cells are transplanted into the muscle near the diseased part, whereafter they differentiate into vascular endothelial cells to form blood vessels. Although its efficacy will have to be evaluated in an increased number of patients, this therapy is expected to become a promising one, because it can treat severe cases. However, one of the problems with this therapy is considered to be a great burden associated with bone marrow harvest which falls on both the patients and the medical staffs.
Recent studies have shown that hematopoietic stem cells, which can differentiate into vascular endothelial cells, are present not only in the bone marrow, but also in the peripheral blood, and they take part in angiogenesis (Qun Shi et al. Blood Vol. 92, 362-367;1998, Takayuki Asahara et al. Circulation Research Vol. 85, 221-228;1999, Mario Peichev et al. Blood Vol. 95, 952-958;2000). (The hematopoietic stem cells are called “precursor cells for endothelial cells” from the viewpoint of the function of differentiating into endothelial cells. However, these cells are originally derived from hematopoietic stem cells. Thus, the term “hematopoietic stem cells” is used herein in accordance with the concept that they are a cell population capable of becoming endothelial cells.) Hence, hematopoietic stem cells in the peripheral blood are harvested and transplanted into the muscle close to the diseased part, whereby treatment of obstructive arteriosclerosis can be expected. This procedure is advantageous in that the burden imposed on the patient and medical staff at the time of taking peripheral blood stem cells is less than that during transplantation of stem cells in the bone marrow. Normally, however, the frequency of hematopoietic stem cells in the peripheral blood is extremely low. Thus, it is highly questionable whether a necessary and adequate amount of hematopoietic stem cells for the treatment of obstructive arteriosclerosis can be obtained.